tbuckley/cabot-search huggingface dataset:
P10.22.B COMBINATION OF ARTS MIMETICS WITH AUTOPHAGY INHIBITORS AS A NOVEL THERAPEUTIC STRATEGY TO OVERCOME APOPTOSIS RESISTANCE IN GLIOBLASTOMA
Authors: H Kuzmychova, E Martell, V Yathindranath, H Senthil, E Kaul, D Miller, S K Singh, T Sharif
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Glioblastoma (GBM) is the most common malignant brain tumour in adults. The current standard of care for GBM patients consists of maximal surgical resection followed by chemotherapy and radiation. Despite such an aggressive treatment approach, the average 5-year survival rate for GBM patients is approximately 5%. One of the main reasons for poor therapy response in the GBM is resistance to programmed cell death, otherwise known as apoptosis. One of the mechanisms behind apoptosis resistance relies on the upregulation of inhibitor of apoptosis proteins (IAPs) which are known to hinder pro-apoptotic proteins and allow cell survival under abnormal conditions such as severe DNA damage. However, there are natural IAP antagonists such as ARTS which are capable of stimulating cell death by promoting the degradation of IAPs. To harness the pro-apoptotic function of IAP antagonists, small peptide mimetics of ARTS have been developed. This project investigates the efficacy of utilizing ARTS mimetics as a novel strategy to overcome apoptosis resistance in the GBM treatment. MATERIAL AND METHODS This study utilizes patient-derived cells with exogenous gain-of-function (GOF) overexpression to introduce full-length ARTS protein as well as pharmacological small peptide mimetics of ARTS to evaluate the response of GBM cells following the promotion of ARTS activity. We also employ a patient-derived orthotopic xenograft mouse model to test novel combinatorial strategies in vivo, where we used a nanoparticle drug delivery system to ensure treatment delivery across the blood-brain barrier (BBB). RESULTS We found that patient-derived GBM cells were highly resistant to ARTS-induced apoptosis. Further molecular investigation unveiled a novel role of ARTS in the upregulation of autophagy as a resistance mechanism. A combination of ARTS GOF or mimetic peptides with autophagy inhibitors mitigated resistance to ARTS-mediated apoptosis and drastically decreased GBM cell proliferation. This combination was further tested in the patient-derived xenograft mouse model, which demonstrated the successful delivery of ARTS mimetic peptides and autophagy inhibitors through the BBB via nanoparticle lipid carriers. Animals treated with a combination of the autophagy inhibitor Spautin-1 and ARTS mimetic peptides demonstrated significantly prolonged survival, confirming the therapeutic potential of such combinatorial approach for GBM treatment. CONCLUSION Altogether, these findings uncover a previously unknown role of ARTS in autophagy regulation and provide evidence that the combination of IAP-antagonist mimetics with autophagy inhibitors can be an effective strategy against highly aggressive GBM brain tumours. This work was supported by the Health Sciences Centre Foundation (HSCF).
PL01.4.A LATE BREAKING ABSTRACT: A LONG PEPTIDE VACCINE TARGETING THE CLONAL DRIVER MUTATION H3K27M IN ADULT PATIENTS WITH DIFFUSE MIDLINE GLIOMA
Authors: N Grassl, I Poschke, K Lindner, K Kromer, L Bunse, I Mildenberger, K Jaehne, G Haltenhof, C Tan, E Green, T Kessler, A Suwala, F Sahm, P Eisele, M Breckwoldt, P Vajkoczy, O Grauer, U Herrlinger, J Tonn, M Denk, M Bendszus, A von Deimling, F Winkler, W Wick, J Lindner, M Platten, K Sahm
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Clonal and mutually exclusive substitution of lysine 27 to methionine in histone H3-3A (H3K27M) defines an aggressive subtype of diffuse glioma. These diffuse midline gliomas (DMG) are aggressive, incurable primary brain tumors that occur predominantly in a midline location in children and young adults. Surgical treatment options remain limited, response to chemoradiation is poor and palliative radiotherapy remains the only intervention with proven benefit, resulting in a median overall survival between 10 and 15 months after initial diagnosis. Previous studies have shown that a H3K27M-specific long peptide vaccine (H3K27M-vac) induces mutation-specific immune responses capable of controlling H3K27M+ tumors in a major histocompatibility complex (MHC)-humanized mouse model. MATERIAL AND METHODS Here we describe the first-in-human treatment with H3K27M-vac of eight adult patients with recurrent H3K27M+ DMG. Induction of mutation-specific immune responses was determined in peripheral blood using Interferon-γ ELISpot assays. Class II HLA-restricted peripheral H3K27M-specific T cells were expanded in vitro to characterize and track unique H3K27M-reactive T cell responses in blood and cerebrospinal fluid (CSF). RESULTS Repeat vaccinations with H3K27M-vac were safe and induced mutation-specific immune responses in five of eight patients after a median of two vaccinations. Median progression free survival after start of vaccination was 6.2 months and median overall survival was 12.8 months. In vitro restimulation of peripheral CD4+ and CD8+ T cells with H3 mutant peptide or wild type peptide revealed that H3K27M specific immune responses are CD4-mediated and can be suppressed by blocking antibodies against MHC II, but not MHC I. Furthermore, proximity ligation assay of formalin-fixed paraffin-embedded primary tumor tissue revealed that H3K27M neoepitope co-localizes with HLA class II-DR. One patient showed radiographic pseudoprogression (PsPD) according to iRANO criteria within six weeks after first detection of mutation-specific peripheral immune response. Following PsPD, three out of the top ten vaccine-induced, K27M-expanded CD4+ TCR clonotypes from peripheral blood were detectable in the CSF of this patient who went into sustained complete remission for &amp;gt; 31 months. CONCLUSION H3K27M-vac is safe and induces H3K27M-specific CD4 T cell responses in patients with H3K27M+ DMG. An ongoing multicenter, phase 1 clinical trial for adult patients with newly diagnosed H3K27M+ DMG will assess the safety and immunogenicity of H3K27M-vac in combination with atezolizumab in standard-of-care radiotherapy (NCT04808245).
OS09.6.A A MULTICENTER, PHASE I/II, OPEN-LABEL STUDY OF INTRATHECAL PEMETREXED FOR LEPTOMENINGEAL METASTASES FROM SOLID TUMOR (PMLM, NCT 05289908)
Authors: Z Pan, G Yang, Z Wang, L Shen, X Pang, T Yuan, S Li, L Dong
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND There has never been a dose-escalation study on intrathecal pemetrexed (IP) with vitamin supplementation. This phase I/II study was to evaluate the maximum-tolerated dosage (MTD) of IP with vitamin supplementation and the antitumor activity for leptomeningeal metastases (LM) from solid tumors. MATERIAL AND METHODS Phase I study followed the classic 3 + 3 design, with the dose of IP escalated from 15 mg. Phase II followed the Simon 2-stage design with the recommended dose determined in phase I. IP was administered twice per week for 2 weeks (induction therapy), followed by once per week for 4 weeks (consolidation therapy). Clinically stable or improved patients continued IP once a month (maintenance therapy). Vitamin B12 (1000 μg) and folic acid (400 μg, q.d.) were given at the beginning of treatment. Primary end points were MTD in phase I and clinical response rate (CRR) in phase I/II. All patients were assessed to investigate safety, CRR and overall survival (OS). RESULTS Between Feb 2022 and Jan 2023, 34 patients (male: 16; female: 18; age: 45-68 years; median: 56 years) were enrolled, including non-small lung cancer (20), small-cell lung cancer (3), breast cancer (8), others (3). Thirty-three patients had a confirmed LM diagnosis (positive CSF cytology). Remaining one had probable diagnosis (positive neuroimaging with typical clinical signs). Ten patients were enrolled in phase I. Three of 4 patients receiving IP at 15 mg completed induction and consolidation treatment without dose limiting toxicity (DLT). The dose was escalated to 20 mg. Two DLT (1 grade 4 hematologic toxicity and 1 grade 5 arachnoiditis) occurred in 6 patients at 20 mg. The MTD was determined to be 15 mg. Then 24 patients were enrolled in phase II and given 15 mg of IP. 82.4% (28/34) and 58.8% (20/34) patients completed induction and consolidation therapy, respectively. 41.2% (14/34) patients received maintenance therapy. Adverse events (AEs) rate was 73.5% (25/34). 50% (17/34) patients showed grade ≥ 3 AEs, including myelosuppression (11), elevation of hepatic aminotransferases (EHA) (5), elevation of blood bilirubin (EBB) (1), arachnoiditis (1), radiculitis (1), fatigue (1) and nausea (1). The overall CRR was 41.2% (14/34) by neuro-oncology proposal criteria, including 10 (29.4%) with improved neurological dysfunction, 11 (32.4%) with CSF cytological response and 4 (11.8%) with neuroimaging improvement. In a total of 28 patients receiving IP at 15 mg, 50% (14/28) patients showed grade ≥ 3 AEs, including myelosuppression (9), EHA (10), fatigue (1) and nausea (1). The CRR was 46.4% (13/28) in patients at 15 mg IP. Median survival was 7.6 (range 0.3-13.7) months in phase I, while has not yet been achieved in phase II until March 15, 2023. CONCLUSION MTD of IP was 15 mg with folic acid and vitamin B12 supplementation. IP is an optimal therapeutic option for LM from solid tumors.
P11.32.A GLIOBLASTOMA NOMOGRAM: PREDICTING THE LOCATION OF FIRST PROGRESSION AFTER LONG-COURSE CHEMORADIOTHERAPY BASED ON A NATIONAL COHORT
Authors: A M Clarke, S Lukacova, R H Dahlrot, C A Haslund, A Muhic, B M Bibby, A K Trip
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Glioblastoma (GBM) is known for its high local failure rate, as well as its migration, leading to these possible locations of disease progression: 1. Local-only; lesion of progression is connected to the initial tumour location 2. Non-local; lesion of progression is not connected to the initial tumour location 3. Combined; both local-only and non-local progression lesions are present An upfront prediction of progression location could potentially be used to select patients for differential treatment strategies. The aim of this retrospective national study was therefore to predict location of first progression using clinical variables. MATERIAL AND METHODS All adults with newly diagnosed GBM between 2014-2019 who started long-course (chemo)radiotherapy were included, if they had a radiotherapy-planning MRI made. The MRI of first progression was identified by retrospective review following RANO-criteria, and used to assess the location of contrast-enhancing progression. Median time to progression (TTP) and survival beyond progression were estimated using the Kaplan-Meier method (log rank test for comparison). To predict location of progression in subgroups of patients, we used a multivariable multinomial model (age, biological sex, performance status, tumour location &amp; focality &amp; laterality, MGMT-methylation status, and extent of surgery). RESULTS We included 940 patients (MGMT methylated n=376, unmethylated n=483, not reported n=81), of whom 760 had radiographic progression. Of those, progression location was local-only in 69%, non-local in 16%, and combined in 15%. Median (95% CI) TTP in months was shortest in the combined group (8.4, 7.3-9.4), followed by the local-only (9.2, 8.5-9.8) and non-local (13.9, 12.3-15.6) (p-value &amp;lt;.001). Survival beyond progression in months was shortest in the combined group (5.0, 3.8-6.2), followed by the non-local (6.0, 4.4-7.6) and local-only (9.0, 8.3-9.7) (p-value &amp;lt;.001). When comparing patients with MGMT-methylated and unmethylated tumours, the probability (95%CI) of local-only progression was .67 (.62-.73) vs. .73 (.69-.78), non-local was .21 (.17-.26) vs. .11 (.08-.14), and combined was .12 (.08-.15) vs. .16 (.12-.19). In the multivariable model, the probability (95%CI) of local-only progression varied from .49 (.29-.69) to .86 (.74-.97), of non-local from .04 (.00-.09) to .34 (.15-.53), and of combined from .05 (.01-.10) to .34 (.07-.60) between respective subgroups. CONCLUSION Location of progression was associated with time to progression and survival beyond progression. In our study population it was feasible to identify subgroups of patients with a high chance of local-only progression, who may potentially benefit most from radiation dose-escalation. Both patients with MGMT-methylated and unmethylated tumours had the highest chance for first progression located at the initial tumour site only.
OS12.6.A PRELIMINARY RESULTS FROM COPENHAGEN STUDY ON QUALITY OF LIFE IN YOUNG ADULTS WITH GLIOMAS
Authors: K Arnkjær, M Bruun-Pedersen, J Skjøth-Rasmussen
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Young patients diagnosed with gliomas face a life-changing disease, with a limited life length. They face challenges participating in daily social life and educational/work life. While the therapy for this patient group has the goal of prolonging life-length, little is known of their quality of life (QoL). A potential lower QoL due to diagnosis and the side effects of the treatment needs to be continuously assessed by health professionals. This study aimed to assess the QoL over time in young patients diagnosed with gliomas and to elucidate if these patients may need additional help and support. A second aim was to test the feasibility of repeated use of two validated online questionnaires to guide the clinicians working with this patient group. A third aim was to calculate a clinical cut-off score for the Functional Assessment of Cancer Treatment-Brain (FACT-Br). MATERIAL AND METHODS The design was a longitudinal, prospective study with a continuous inclusion during a 3-year period (2020-2023). Patients included were 18-35 years old suspected with a low-grade glioma at their first consultation in the clinic. The QoL was evaluated using FACT-Br and WHO-5 (WHO-5 Well-Being Index). The patients received the online questionnaires at pre-selected time points (pre-operation, 3-month, 6-month, 12-month) followed by a 3-month break and then repeated. The feasibility was evaluated in terms of compliance over time, defined as a completion of the first consecutive four questionnaires. A linear Generalized Estimating Equation (GEE) analysis was used to identify changes in FACT-Br total score. RESULTS A total of 33 patients were included in the study (Mdn=26y; 60% men; drop-out/exclusion n=3). At 3-month follow-up (n=30) four patients (13,3%) had a WHO-5 score below cut-off value (50/100 points) and five patients (16,7%) had a FACT-Br score below calculated cut-off (144/200 points) (M=160). The cut off-score for FACT-Br was calculated using a ROC-curve based on the WHO-5 cut-off value (n=30). The quality was deemed good (AUC=0,895). The Fact-Br total score showed no significant change over time (n=30). One subscale regarding functional wellbeing did show a significant change (p=0.021) (180 days change = 0,74; 95%-CI: 0,39-1,09). In March 2023 11 of 13 (84,6%) patients had a complete set of the first four consecutive questionnaires. CONCLUSION There was no significant change in the overall QoL (FACT-Br), but one subscale improved significantly. Five patients had a FACT-Br score below the calculated cut-off at 3 month-follow-up which might indicate a need for further support. Our study suggests that online QoL questionnaires are feasible in a clinical setup with this patient group. These results may give health professionals better insight in the need of support thus securing the best quality of life possible in young patients waiting for disease progression.
P03.03.A T2-FLUID-ATTENUATED INVERSION RECOVERY MISMATCH SIGN IN LOWER-GRADE GLIOMAS: CORRELATION WITH PATHOLOGICAL AND MOLECULAR FINDINGS
Authors: S Yamashita, H Takeshima, Y Kadota, M Azuma, T Fukushima, T Watanabe, K Yokogami
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND After the new molecular-based classification was reported to be useful for predicting prognosis, the T2-fluid-attenuated inversion recovery (FLAIR) mismatch sign has gained interest as one of the promising methods for detecting lower-grade gliomas (LGGs) with isocitrate dehydrogenase (IDH) mutations and chromosome 1p/19q non-codeletion (IDH mut-Noncodel) with high specificity. Although all institutions could use T2-FLAIR mismatch sign without any obstacles, this sign was not completely helpful because of its low sensitivity. In this study, we attempted to uncover the mechanism of T2-FLAIR mismatch sign for clarifying the cause of this sign’s low sensitivity. MATERIAL AND METHODS In this study, data on 101 consecutive and unselected patients with LGGs (WHO grades 2 and 3) admitted to Miyazaki University Hospital between November 2005 and January 2021 were collected. The inclusion criteria were as follows: (1) obtained molecular information on IDH mutation and chromosome 1p/19q codeletion status and (2) obtained preoperative MRI data, including T2-weighted imaging and FLAIR sequences. In this study, 99 patients were enrolled and then classified into three groups based on IDH mutation and chromosome 1p/19q codeletion status: (1) IDH-mutant, 1p/19q-codeleted LGGs (IDH mut-codel); (2) IDH-mutant, 1p/19q-noncodeleted LGGs (IDH mut-Noncodel); and (3) IDH wild-type LGGs (IDH wt). RESULTS Among 99 patients with LGGs, 22 were T2-FLAIR mismatch sign-positive (22%), and this sign as a marker of IDH mut-Noncodel showed a sensitivity of 55.6% and specificity of 96.8%. Via pathological analyses, we could provide evidence that not only microcystic changes but the enlarged intercellular space was associated with T2-FLAIR mismatch sign (p =0.017). As per the molecular analyses, overexpression of mTOR-related genes (m-TOR, RICTOR) were detected as the molecular events correlated with T2-FLAIR mismatch sign (p = 0.020, 0.030. respectively). CONCLUSION We suggested that T2-FLAIR mismatch sign could pick up the IDH mut-Noncodel LGGs with enlarged intercellular space or that with overexpression of mTOR-related genes.
P16.08.A SINGLE-CELL MAPPING OF LEPTOMENINGEAL DISEASE IN GLIOBLASTOMAS
Authors: R Sankowski, A Dalmau Gasull, A Khavaran, J Cahueau, M Prinz
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND The leading edge of glioblastomas is characterized by the crowding of neoplastic cells around neurons and inside the perivascular space, a phenomenon known as satellitosis. Recent research has focused on the interaction between glioblastoma cells and neuronal networks, but the specific cells contributing to perivascular satellitosis have not been comprehensively studied. MATERIAL AND METHODS To address this gap, we conducted single-nucleus RNA sequencing on glioblastoma samples, dissecting the leptomeninges and tumor core from freshly resected tissue. As the brain parenchyma and perivascular space cannot be easily separated, we sampled tumor cells from the leptomeninges, the outer limit of the perivascular space. This approach harnesses the fact that the subarachnoid and perivascular spaces are directly connected. Thus, we could isolate perivascularly located tumor cells. RESULTS Our analyses revealed distinct transcriptional signatures between tumor cells from the leptomeninges and those from the tumor core. Tumor core-associated cells showed transcriptional programs related to hypoxia and collagen expression, while leptomeningeal tumor cells displayed programs related to axonal guidance, synaptic function, and extracellular matrix expression. Interestingly, there was significant overlap with previously published gene expression programs found in tumor cells integrating into neuronal circuits. Cell-cell interaction analysis identified interaction between tumor cells and the resident cell types of the perivascular space, including fibroblasts, perivascular macrophages and lymphocytes. CONCLUSION Our study provides a robust methodology for high-dimensional analysis of glioblastoma cells spreading through the perivascular space in human patients. Using this methodology we shed light on the biological processes of perivascular satellitosis and the spread of glioblastoma cells via pre-existing anatomical niches. Due to the distinct cellular composition of the perivascular space, the biology of satellitosis is distinct from the processes in the parenchyma. These findings have important implications for the development of targeted molecular therapies for glioblastomas.
P04.01.B MEK INHIBITORS IN PEDIATRIC RECURRENT SYMPTOMATIC UNRESECTABLE LOW-GRADE GLIOMAS HARBORING MAPK ALTERATION: A SINGLE CENTER EXPERIENCE
Authors: C Fonte, B Castelli, M Tellini, M Guidi, L Giunti, M Di Nicola, A Buccoliero, C Caporalini, F Giordano, F Mussa, L Genitori, I Sardi
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Treatment of inoperable, recurrent, progressive pediatric low-grade gliomas (pLGGs) remains controversial. Recent studies focused on aberrant activation of the mitogen-activated protein kinase (MAPK) pathway, due to gain of function mutations in RAS or BRAF genes or loss or inactivation of NF1. Selumetinib and trametinib, orally bioavailable and selective MEK1/MEK2 inhibitors (MEKi), act on MAPK pathway. In April 2020 the US Food and Drug Administration and in June 2021 the European Medicines Agency approved selumetinib for inoperable plexiform neurofibromas in Neurofibromatosis type 1 (NF1). We evaluated MEKi efficacy and safety in pLLGs harboring MAPK alteration. MATERIAL AND METHODS From July 2021 to February 2023 eight patients (5 females, 3 males, median age 8 years, range 4-18) were admitted to our hospital for symptomatic, recurrent, inoperable pLGGs (location: 3 hypothalamic-optic chiasm region, 2 posterior fossa, 1 temporo-mesial, 1 quadrigeminal plate, 1 diffuse leptomeningeal; MAPK alteration: 3 NF1 inactivation, 4 KIAA1549/BRAF gene fusion, 1 RNF130/BRAF fusion). MEKi were administered (6 selumetinib, 2 trametinib) after disease progression for failure of previous treatments (6 partial resection, 7 multiple chemotherapies, 2 radiotherapy). MRI assessment was performed every 4 months and radiological response was defined in accordance with RAPNO criteria. RESULTS At first evaluation, 3/8 patients (37,5%) showed a partial radiological response (-64,96% mean volume reduction, range 52,61%-77,19%) and 4/8 (50%) stable disease (0-41.67% volume decrease). Disease progression was observed in a patient heavily pretreated for acute leukemia. One patient with leptomeningeal spreading showed progressive disease at second evaluation. Median time to progression has not yet been reached. Six of 8 patients experienced at least one toxicity. The most frequent toxicities reported were mucocutaneus disorders (rash, mucositis, eczema). Three patients presented creatine phosphokinase (CPK) increase (one grade 2 with rapid normalization after therapy discontinuation). All patients on trametinib had to reduce treatment dose (for skin toxicity or increasing blood pressure). CONCLUSION MEKi, selumetinib and trametinib, represent promising strategies in children with recurrent/progressive LGGs harboring MAPK alterations. In our small series, the treatment was effective and well tolerable in patients with localized disease and without other risk factors. The most common toxicities were CPK elevation and rash. Further studies are needed to identify patients who may benefit most from MEKi treatment and to establish whether such treatments are superior to chemotherapy in front line setting for MAPK altered pLGGs.